title: Cannabinoid receptor 2 counteracts interleukin-17-induced immune and fibrogenic responses in mouse liver.
abstract: Interleukin (IL)-17 is a proinflammatory and fibrogenic cytokine mainly produced by T-helper (Th)17 lymphocytes, together with the hepatoprotective and antifibrogenic cytokine, IL-22. Cannabinoid receptor 2 (CB2) is predominantly expressed in immune cells and displays anti-inflammatory and antifibrogenic effects. In the present study, we further investigated the mechanism underlying antifibrogenic properties of CB2 receptor and explored its effect on the profibrogenic properties of IL-17. After bile duct ligation (BDL), the hepatic expression of Th17 markers and IL-17 production were enhanced in CB2(-/-) mice, as compared to wild-type (WT) counterparts, and correlated with increased fibrosis in these animals. In contrast, IL-22-induced expression was similar in both animal groups. Inhibition of Th17 differentiation by digoxin lowered Th17 marker gene expression and IL-17 production and strongly reduced liver fibrosis in CB2(-/-) BDL mice. In vitro, differentiation of CD4(+) naïve T cells into Th17 lymphocytes was decreased by the CB2 agonist, JWH-133, and was associated with reduced Th17 marker messenger RNA expression and IL-17 production, without modification of IL-22 release. The inhibitory effect of JWH-133 on IL-17 production relied on signal transducer and activator of transcription (STAT)5 phosphorylation. Indeed, STAT5 phosphorylation and translocation into the nucleus was enhanced in JWH133-treated Th17 lymphocytes, and the addition of a STAT5 inhibitor reversed the inhibitory effect of the CB2 agonist on IL-17 production, without affecting IL-22 levels. Finally, in vitro studies also demonstrated that CB2 receptor activation in macrophages and hepatic myofibroblasts blunts IL-17-induced proinflammatory gene expression.
  
  
  CONCLUSIONS
  These data demonstrate that CB2 receptor activation decreases liver fibrosis by selectively reducing IL-17 production by Th17 lymphocytes via a STAT5-dependent pathway, and by blunting the proinflammatory effects of IL-17 on its target cells, while preserving IL-22 production.
authors.affiliation: Inserm, U955, Créteil, France; Université Paris-Est, Faculté de Médecine, UMR-S955, Créteil, France.
authors.forename: Adrien
authors.initials: A
authors.lastname: Guillot
authors.forename: Nabila
authors.initials: N
authors.lastname: Hamdaoui
authors.forename: Alexandra
authors.initials: A
authors.lastname: Bizy
authors.forename: Keve
authors.initials: K
authors.lastname: Zoltani
authors.forename: Rachid
authors.initials: R
authors.lastname: Souktani
authors.forename: Elie-Serge
authors.initials: ES
authors.lastname: Zafrani
authors.forename: Ariane
authors.initials: A
authors.lastname: Mallat
authors.forename: Sophie
authors.initials: S
authors.lastname: Lotersztajn
authors.forename: Fouad
authors.initials: F
authors.lastname: Lafdil
mesh_terms: D000818:Animals; D001652:Bile Ducts; D020381:Interleukin-17 / Q000378:metabolism*; D007378:Interleukins / Q000378:metabolism; D008026:Ligation; D008103:Liver Cirrhosis / Q000276:immunology* / Q000378:metabolism*; D008264:Macrophages / Q000502:physiology; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D058628:Myofibroblasts / Q000502:physiology; D043885:Receptor, Cannabinoid, CB2 / Q000378:metabolism*; D050799:STAT5 Transcription Factor / Q000378:metabolism; D058504:Th17 Cells / Q000378:metabolism*; D000097043:Interleukin-22
chemical_list: D020381:Interleukin-17; D007378:Interleukins; D043885:Receptor, Cannabinoid, CB2; D050799:STAT5 Transcription Factor; D000097043:Interleukin-22